Method of treating depression

ABSTRACT

The monamine oxidase inhibitor drug L-deprenyl (phenylisopropyl methyl propynyl amine) is safely and conveniently used for the treatment of mental depression in a formulation applied to the skin of the patient. In this way the danger of side reaction due to the consumption of foods containing tyramine (the cheese effect) is minimized. Unlike other monamine oxidase drugs, such as Parnate, L-deprenyl does not cause skin irritation when used in this way.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of my copending application Ser. No.07/086,795, filed 18 Aug. 1987.

FIELD OF THE INVENTION

My present invention relates to the therapeautic administration of thedrug L-deprenyl a method of treating human subjects suffering fromdepression and, more particularly, to (levo phenyl isopropyl methylpropynyl amine) for this purpose. For brevity, L-deprenyl will often bedenoted below as LDY.

BACKGROUND OF THE INVENTION

Two general classes of organic pharmaceuticals useful in the treatmentof the mental disease depression in humans have been recognized: (1)tricyclic antidepressants, as exemplified by amitriptyline andprotriptylene, and (2) monoamine oxidase inhibitors (MAOI), asexemplified by the commercially available drugs Nardil, Parnate, andL-deprenyl.

Both types of drugs are generally regarded as effective, but both haveundesirable side effects. For tricyclic drugs, recognized side effectsinclude dry mouth, orthostatic hypotension, and impotence, and theseeffects are frequent. The most significant side effect of the MAOI drugsis a rare but serious one: sudden and dangerous life-threateningelevation of blood pressure when the patent taking such drugs alsoconsumes foods high in the naturally occurring substance tyramine.Cheese is the most common food containing large amounts of tyramine, sothat this side effect is often known colloquially in the medicalprofession as the "cheese effect."

Because the cheese effect can cause very serious medical problems,including death in severe cases, MAOI drugs are little used, even thoughthey are generally free from the other more common side effects of thetricyclic drugs and are believed to have at least equal effectiveness inthe treatment of most types of depression.

Tyramine is known to be capable of causing severe hypertension whenpresented in the blood, but it is normally converted in thegastrointestinal tract by the action of a monoamine oxidase enzymenaturally present there, to other substances incapable of causingdangerous hypertension. When a patient is taking an MAOI orally,however, deactiviation of the tyramine by gastrointestinal enzymes is atleast partially repressed, and serious clinical symptons may result.

Recent research has recognized a distinction among the MAOI drugsthemselves, connected with recognition of the existence of two isozymesof monoamine oxidase itself, denoted simply as the A and B isozymes.Nardil and Parnate are recognized as primarily inhibitors of the actionof monoamine oxidase A, while deprenyl first inhibits the action ofmonoamine oxidase B and significantly inhibits the action of monoamineoxidase A only at larger doses. The tyramine deactivating monoamineoxidase enzyme is primarily type A, so that it would appear thatadministration of L-deprenyl should not induce the cheese effect. Thecheese effect, however, is potentially so serious that, the use ofL-deprenyl in an oral dosage is nevertheless counterindicated simplybecause it does appear to have some MAO-A inhibiting activity. On theother hand, the monoamine oxidases in the brain are primarily of the Btype, so that LDY is very effective in inhibiting their action.

There are three general modes of administration which have been used forthe antidepressants under consideration, which must reach the bloodstream in the course of exerting their therapeutic effects: oral,intravascular, and transdermal. Because of the danger of infection andthe need for trained personnel for administration, intravascularadministration is disfavored when one of the other two means iseffective. Drugs for treating depression have traditionally beenadministered orally, but transdermal administration of some of thetricyclic antidepressant drugs, and by implication, any suitable drug,has also been taught by U.S. Pat. No. 4,230,105 of Oct. 28, 1980 toHarwood. Transdermal administration of drugs in general has been taughtby earlier patents, including some cited in the Harwood reference.

One highly restrictive limitation on the transdermal administration ofdrugs is the possibility of skin irritation or allergic reactionsinduced by such administration. This is particularly important whenconsidering treatment of depression since MAO inhibitors are required tobe used at higher dose levels.

In Whatever dosage form it may be administered, an antidepressant drugmust be constantly present in the body for up to six months if thepatient is to derive maximum benefit and not revert to a depressedstate.

If transdermal administration of an antidepressant is to be used, thismeans very prolonged and constant or near-constant contact between thepatient's skin and the pharmaceutical including the drug. It is wellknown that long-term exposure of skin to a chemical substance even atlow dosages often will result either in a local skin inflammation at theside of contact or a more general immunologically based allergicreaction that can have a serious adverse effect on the entire body. Wheneither of these events occurs. the affected patient should immediatelydiscontinue contact with the offending agent. Since MAO inhibitorsgenerally were found heretofore to be skin irritants, clearly their usefor antidepression treatment by transdermal techniques was notindicated.

SUMMARY OF THE INVENTION

I have found, most surprisingly, that LDY, applied to a suitable formand amount to human skin, is readily absorbed through the skin into thebloodstream to achieve and maintain a level in the blood, including theblood in the brain, which is effective in the treatment of depression.

Furthermore, while other MAO inhibitors are highly irritating to theskin, surprisingly, it has been found that LDY causes little or no skinirritation, by contrast with Parnate, for example, which is stronglyirritating to the skin. Thus, transdermal administration of LDY providesa surprisingly nonirritating and effective method for treatingdepression.

SPECIFIC DESCRIPTION

For a normal human adult, about 30 mg of deprenyl per day is normally aneffective dose for relief of depression. This may be adjusted to bloodvolume of a particular patient by calculations well-known in the medicalarts. The drug is preferably used either as free base or as itshydrochloride. For convenience in dispensing, the drug usually is mixedwith other pharmaceutically inert materials. These inert materials, alsocalled excipients, can be formulated by methods known in the prior artso as to promote either rapid absorption of most of the drug contentapplied to the skin, or a slower absorption over a longer time.

In treating most patients for depression, it is preferable to use aformulation which will result in an approximately constant level of theantidepressant drug in the blood supply to the brain. After a possiblydifferent initial treatment, such a constant level of drug in the bloodwill normally result from a constant rate of absorption from the applieddrug mixture through the patient's skin into the bloodstream.

A mixture of LDY with appropriate excipients may effectively be utilizedin a skin patch structure, of any of several types known to the artwhich will maintain the drug mixture in effective contact with the skin,protect against deteriorations in the drug which might be caused by suchcommon causes as air oxidation, moisture absorption or loss, etc., andstay in position under normal conditions of patient mobility andbathing. The prepared patch structure, including a mixture of LDY incontact with the skin, may be applied to the skin of a patient in any ofthe locations on the body conventionally used for application oftransdermal medications.

In order to promote consistent therapy with poorly motivated, easilydistracted, or otherwise less-than-ideally-attentive patients--typesparticularly likely to be countered in the treatment of depression--itis advantageous for the supply of LDY in a single therapeutic structureto last for at least one full day. Structures lasting several days, oreven weeks, are still more preferable as they require less patientattention.

The scope and nature of the invention may be further appreciated fromthe following non-limiting examples. In all the examples, allspecifications of parts and percentages in formulations refer to partsand percentages byweight, and the dosage specified may be adjusted tothe exact needs of an individual patient and accurately dispensed byconventional techniques known in the medical arts.

EXAMPLE 1

A suitable mixture for treatment according to this invention, consistsof 3parts of L-deprenyl mixed with 97 parts of an ointment base. Thecomposition of the ointment base is as follows:

    ______________________________________                                        Polyethylene glycol 6000 distearate                                                                  5-15%                                                  Polyethylene glycol 1540                                                                             15-25%                                                 Butylated hydroxytoluene preservative                                                                0.1-.1-0-5%                                            Polyethylene glycol 300                                                                              Balance                                                ______________________________________                                    

An amount of 0.5 to 2.0 grams of this medicated ointment is applied tothe forearm of a patient suffering from depression and rubbed into theskin toprovide a therapeutically effective amount of L-deprenyl for atleast one day.

EXAMPLE 2

This is the same as Example 1, and is used in the same way, except thatthebase is a cream rather than an ointment. The composition of the creambase is:

    ______________________________________                                        Glyceryl monostearate NF VII                                                                       10-20%                                                   Cetyl alcohol        5-10%                                                    Cetyl ester wax      5-10%                                                    Polysorbate 60       5-10%                                                    Propylene glycol     5-10%                                                    Dimethicone 350      0.5-3%                                                   Paraban preservative 0.2%                                                     Water                Balance                                                  ______________________________________                                    

EXAMPLE 3

This is an example of a transdermal patch incorporating LDY. Five tofifty milligrams of this drug is dissolved in a mixture of mineral oiland poly (isobutylene) to provide a liquid-center reservoir of activedrug. This reservoir is enclosed in a sealed, flat disc-shaped pouch,one to six centimeters in diameter. The top of the pouch consists of athin aluminized polyester film that is impermeable to the pouchcontents. The bottom of the pouch that will be in contact with the skinin use consists of thin polypropylene membrane that is slowly porous toLDY, allowing the drug to continuously come into contact with the skin,so long as the bottom of the pouch is in contact with the skin. Thisbottom of the pouch also includes a thin coat of a hypoallergenicsilicone adhesive disposed on the bottom in such a way as to hold thepatch firmly to the skin without unduly impeding the permeation of thedrug through the membrane. As manufactured, a protective strip ofsiliconized polyester film covers the polypropylene membrane. Thissiliconized film is impermeable to the liquid mixture and thus protectsthe pouch's therapeutic contents during storage. The protective film isremoved by the patient prior to the attachment of the patch to the skin.

EXAMPLE 4

The general construction of the therapeutic device for this example isthe same as for Example 3, except that (1) the LDY is mixed with 50 mgof lactose, 50 mg of finely divided silicon dioxide, and 0.1 to 0.4milliliters of medical-grade silicone fluid to form the reservoir ofactive drug and (2) the bottom of the patch consists of a thinethylene-vinyl acetate copolymer membrane. The product is used in thesamemanner as in Example 3.

EXAMPLE 5

For this example, a solution or finely divided emulsion of L-deprenyl isprepared in a dispersion in water, or alternatively in a co-dispersionwith a binder such as polyvinyl chloride. Geon 576, a product of B. F.Goodrich, is a suitable dispersion of binder into which LDY can bedo-dispersed. The emulsion is dried onto a thin solid film of polyvinylchloride or polypropylene plastic, which is slowly permeable to LDY togive a flat disc 1 to 6 centimeters in diameter. The top surface of thepatch, the provision of a protective cover on the bottom for storage,and the optional use of a hypoallergenic adhesive on the outside of thebottomof the patch are the same as in the previous examples. The type ofskin patch used for this example is described in more detail in U.S.Pat. No. 4,284,444.

It is well known in the medical arts that a patch maintained in tightcontact with the skin will provide an occlusive cover. This will inducechanges in the cellular architecture of the skin, including an increaseinits water content. These changes allow LDY to migrate from the driedreservoir in the patch through the skin into the systemic bloodcirculation.

I claim:
 1. A method of treating depression in a human patient whichcomprises maintaining in contact with the skin of said patient aquantity of L-deprenyl or a salt thereof in a form permitting migrationof said L-deprenyl or salt thereof through the skin of said patient intothe bloodstream of the patient to a sufficient extent to produce atherapeutically effective amount of L-deprenyl within the blood supplyto the brain of said patient without causing skin irritation to thepatient or inducing a cheese effect in the patient.
 2. The methoddefined in claim 1 wherein said L-deprenyl or salt thereof is mixed withan excipient before being applied to the skin of said patient.
 3. Themethod defined in claim 2 wherein said excipient causes the L-deprenylcontent of the mixture to migrate into the bloodstream of the patient ata controlled rate, whereby at least said therapeutically effectiveamount of L-deprenyl is maintained in the blood supply to the brain ofsaid patient continuously throughout a time interval.
 4. The methoddefined in claim 3 wherein said mixture containing L-deprenyl iscontained within a patch structure for convenient affixation to a partof the body of said patient in such a manner as to maintain contactbetween the skin of said patient and said mixture containing L-deprenylduring said time interval.
 5. The method defined in claim4 wherein saidtime interval is at least one day.
 6. A method, according to claim 5,wherein said controlled rate is between 5 and 50 mg of L-deprenyl perday.